Without limiting the scope of the invention, its background is described in connection with application of nitric oxide in medical indications and with compositions and methods for extended nitric oxide (NO) generation and application locally.
The biological importance of NO is well documented. See e.g. Lancaster J R. Proc Natl Acad Sci 91 (1996) 8137-41; Ignarro et al. Proc Natl Acad Sci 84 (1987) 9265-69; reviewed in Bredt D S, J Cell Science 116 (2003) 9-15; reviewed in Murad F, N Engl J Med 355 (2006) 2003-11. In mammals, NO is an endogenous physiological mediator of many processes in the nervous, immune and cardiovascular systems. These include vascular smooth muscle relaxation, which results in arterial vasodilation and increased blood flow. NO is also a neurotransmitter and has been associated with neuronal activity and various functions ranging from avoidance learning to genital erection in males and females (Kim et al., J. Nutrition 134 (2004) 28735). NO also partially mediates macrophage cytotoxicity against microbes and tumor cells. Besides mediating normal functions, NO is implicated in pathophysiologic states as diverse as septic shock, hypertension, stroke, and neurodegenerative diseases.
NO has been applied pharmacologically in various forms. See Butler and Feelisch, Circulation 117 (2008) 2151-59. One must note, however, that NO itself is highly reactive and is not chemically stable in air or in the body. Therefore, its pharmacological applications almost invariably involve its production via a chemical reaction of various individually-stable precursor compounds. Organic and inorganic nitrates acting as NO donors such as nitroglycerin and sodium nitroprusside have long been used to correct NO deficient states or to regulate the activities of many tissues. Topical applications of NO may be used to help wound and burn healing, hair growth, impotence, and to cause vasodilatation where needed (e.g., promoting peripheral blood flow in patients with impaired circulation due to diabetes or other conditions and ripening of the cervix in pregnancy). Local high concentrations of NO (eye, skin, e.g.) are tolerated. Smith et al. (U.S. Pat. No. 5,519,020) describes polymeric nitric oxide sources thought to be useful to promote healing.
In a range of topical applications, a low persistent dose of NO is desired. NO serves as a powerful microbicide that is effective against antibiotic-resistant bacteria. In anti-microbial and other topical applications, the NO needs to be maintained in contact with the skin for an extended period of time. In anti-microbial applications, the therapeutically-effective NO dose can be small, only a few hundred parts per million (ppm) (see, for example, Ghaffari et al., Nitric Oxide Biology and Chemistry 14 (2009) 21-29), but the effectiveness of the NO depends substantially on how long the skin contact is maintained (Omerod et al., BMC Research Notes 4 (2011) 458-465).
A technology for topical release of NO is described in Seitz et al U.S. Pat. No. 6,103,275 and the co-pending application of Seitz et al (U.S. Ser. No. 13/688,511, filed Nov. 29, 2012), which are incorporated herein by reference. However, this technology provides a topical NO dose that lasts for less than one hour, and an alternate approach is needed to provide the lengthy NO skin contact required for many therapeutic applications.